Abstract This proposal seeks to create the Hemonauts suite of interactive digital media (IDM) to serve chronically ill, frequently hospitalized students in grades five through eight and their support networks to (i) Increase STEM content knowledge through gameplay; (ii) Increase knowledge of and intent to persist in STEM careers; and (iii) Increase disease literacy to improve patient self-advocacy, treatment compliance, and to promote healthy lifestyle choices. Chronically ill children are at risk of falling behind in school due to frequent absences and disease implications, potentially resulting in additional psychological complications and long term setbacks. While there are several health-based apps on the market that promote disease management, there is a lack of serious STEM games offered to children with the chronic diseases of Sickle Cell Disease (SCD), Asthma, and Diabetes. Hemonauts leverages these diseases as an entry point to exploit the target population's innate interest in anatomy and physiology, leading to not only a greater understanding of patients' diseases but also an increase in STEM content knowledge through newly designed, adaptive math and science challenges and virtual interactions with STEM professionals (e.g., scientists, doctors, roboticists, etc.). Through previous Phase I SBIR funding (R43OD021310), we created and tested a prototype game involving three activities to engage children in challenges related to SCD. Chronically ill student players expressed that the game was captivating and highly needed; however, they did not demonstrate increases in STEM content knowledge and expressed an alarmingly low level of disease literacy. For these reasons, our Phase II grant will lead to the creation of a series of games with supplemental, remedial education materials: a digital graphic and text and/or audio, depending on findings from our research with SCD games, that will strengthen users' abilities to correctly answer challenge questions, complete systems biology missions, and report findings to STEM professionals. Assessing how students, patients, and their families interact with remedial materials in the context of the game, and how usage relates to advancement through the game, will contribute to the growing body of STEM game literature and will answer our research question: What is the optimal mode of delivery for STEM educational content within IDM to promote increases in content knowledge and intent to persist in STEM? Once we understand how players learn STEM and disease-based concepts within IDM, we will apply and extend this knowledge to children with Asthma and Diabetes. This suite of Hemonauts IDM will be piloted with patients receiving in-hospital treatment, their parents, and siblings. Family members can explore diseases via graphic novels and videos and complete STEM missions that simulate real world disease challenges. As additional components, we will offer the Hemonauts games and supplemental materials in both English and Spanish and develop in-app functions to track patient symptoms and appointments, connect with support groups, and communicate non-emergency information to healthcare providers.